Integrated multi-omics analysis identifies candidate eRNA-associated signatures shared between osteoarthritis and...

Area of Science:

• Immunology
• Genomics
• Epigenetics

Background:

• Osteoarthritis (OA) and type 2 diabetes mellitus (T2DM) frequently coexist, sharing underlying inflammatory and metabolic dysregulation.
• Immune-epigenetic features linking OA and T2DM remain poorly understood, particularly concerning enhancer RNAs (eRNAs).

Purpose of the Study:

• To investigate overlapping molecular features, specifically eRNA-associated signatures, between OA and T2DM.
• To identify key transcription factors, candidate genes, and immune patterns shared by these distinct conditions.

Main Methods:

• Analysis of transcriptomic datasets from OA joint tissues and T2DM monocytes.
• Utilized differential expression analysis, Weighted Gene Co-expression Network Analysis (WGCNA), and CIBERSORT.
• Integrated public epigenomic data (ATAC-seq, ChIP-seq, scRNA-seq) and an in vitro high-glucose stress model.

Main Results:

• Identified 473 dysregulated eRNA-associated features in OA, linked to skeletal development, ECM remodeling, and PI3K-Akt signaling.
• Overlapping pathway alterations, including TNF-α/NF-κB and MAPK signaling, were observed between OA and T2DM datasets.
• Prioritized TOB1 as a key eRNA-associated feature linked to JUN, CCNL1, and inflammatory signaling; CCNL1 was commonly downregulated. In vitro, high glucose reduced TOB1, JUN, and CCNL1 protein levels.

Conclusions:

• TOB1 emerges as a critical eRNA-associated signal connecting JUN, CCNL1, and inflammation across OA and T2DM.
• This study provides a bioinformatics framework, supported by epigenomic and in vitro data, for understanding immune-metabolic overlap.
• Highlights potential therapeutic targets for conditions where OA and T2DM intersect.